Synthetic Studies On Trans-3,4-Disubstituted Succinimides And The Asymmetric Total Synthesis Of (3S,5R,8S,9S)-3-Butyl-5-Propyl-8-Hydroxyindolizidine And (-)-Bao Gong Teng A

The 3,4-disubstituted succinimide substructure-containing natural products andindolizidine alkaloids, tropane alkaloids are widespread in nature. Most of themexhibit important bioactivities. Among them,(-)-Bao Gong Teng A was the firsttropane alkaloid found in nature which exhibited cholinergic activity. In clinicalophthalmology, it has been used to treat glaucoma as the miotic agent. Recentlyisolated indolizidine alkaloid 28 was the first reported ring-hydroxylatedacetate-derived ant venom alkaloid. Although the bioactivity of this indolizidinealkaloid has not yet been studied, it has been reported to be involved in ant warfare.For the synthesis of these bioactive natural products, the aim of this dissertation isexploring new methods for the construction of these structure skeleton. The mainresults and observations from these studies are listed as follows:1.A highly trans-stereoselective SmI₂-induced Reformatsky-type reaction of4-substituted-O-benzoylated malimides with carbonyl compounds was performedwith excellent yield. The stereochemistry of compound 21d was determined by singlecrystal X-ray crystallographic analysis and a plausible mechanism for thestereoselective reaction was proposed. 2. An enantiodivergent strategy for the synthesis of trans-3,4-disubstitutedsuccinimides was accomplished. Such a synthetic strategy was achieved by distinctlyusing the dianion aldol-type reaction or the Seebach's protocol in the malimideformation step.3. Starting from the building block 86, the cis-5,6-disubstitutedlactam 99a wassynthesized. 4. A seven-step synthesis of (3S,5R,8S,9S)-3-butyl-5-propyl-8-hydroxyindolizidine(28), an ant venom alkaloid isolated from Myrmicaria melanogaster, was disclosedwith an overall yield of 28.9%. The key feature of the synthesis is the use of theiodocarbamoylation for the introduction of the hydroxyl group of the 3-piperidinol.Remarkably, all the reaction steps proceeded with excellent chemo-, regio-, and/ ordiastereo-selectivities. To the best of our knowledge, while electrophile-mediatedheterocyclization reaction is a popular methodology for the synthesis of heterocyclies,its use in the stereoselective installation of the 3-piperidinol hydroxyl group is rare. 5. Starting from imide 147, a 11-step synthesis of(-)-Bao Gong Teng A was disclosedwith an overall yield of 7.58%. The key step was the SmI₂ mediated intramolecularcoupling of the iminium ion with the aldehyde, which constructed the tropaneskeleton with a diastereoselectivity of 11:1 at C-2 carbinol..